It is known that operations and wounds in the body often brings about inflammation and/or infections, which is the case also in connection with implantations, especially in connection with bone tissue, e g hip joints and dental applications.
When titanium is exposed to air or water, an oxide layer is spontaneously formed. This spontaneously formed oxide layer is 4-10 nm thick and consists predominantly of TiO2, Ti(IV), with smaller amounts of Ti(III) and Ti(II) present in the oxide (se references 1, 3 and 4).
The anti-inflammatory and antibacterial effects of titanium are based on the chemical properties of TiO2 at its surface and may work in several different ways, all related to the exposed surface area. As previously shown (reference 2), TiO2 has the ability to directly scavenge ROS (reactive oxygen species). One possible mechanism is through a set of catalytic redox reactions that has been suggested for the breakdown of hydrogen peroxide, superoxide and peroxynitrite on titanium dioxide surfaces (references 2 and 5):2TiO2+2O2−+2H+→Ti2O3+2O2+H2O  (1a)2TiO2+H2O2→Ti2O3+O2+H2O  (1b)Ti2O3+OONO−→2TiO2+NO2−  (2a)Ti2O3+H2O2→2TiO2+H2O  (2b)
Of special interest with respect to the antibacterial effects of titanium is the possibility that TiO2 may also react directly with H2O2 and form a Ti-peroxy gel, TiOOH(H2O)n, on the oxide surface. ESR (electron spin resonance) measurements have also shown that superoxide radicals are present in the Ti-peroxy gel, indicating either trapping of superoxide in the gel or direct reaction between superoxide and Ti(IV) in the Ti-peroxy gel (references 5-7). Complexes similar to the Ti-peroxy gel might also be formed between TiO2 and peroxynitrite. It was recently shown that peroxynitrous acid, the protonated form of peroxynitrite (pKa=6.8), forms a complex similar to the Ti-peroxy gel with Ti(IV) under acidic conditions (reference 8). Moreover, the blue tint sometimes found in tissue surrounding titanium implants suggests that Ti(IV) reacts with ROS and forms stable Ti(III) complexes (see reference 9). It has also been shown that the thickness of the titanium oxide layer on implants increases with time in vivo (reference 10), suggesting that Ti metal might act as a sink for oxygen species. All of these reactions might be involved in the direct breakdown of ROS that occurs on the TiO2 surface and the linked anti-inflammatory effect.
Titanium (that is titanium metal with a surface layer of titanium oxide) has been reported to reduce inflammation (Overgaard, Danielsen et al. 1998) and also to be less susceptible to infections than other materials (Johansson, Lindgren et al. 1999). There are also reports describing unique properties of titanium due to its chemical interactions with reactive oxygen species (ROS). The catalytic property of titanium has been shown to be related to the titanium oxide on the surface being present on surfaces composed of only titanium oxide (Sahlin 2006 et al). Such a catalytic property is e.g. described in the US patent application No. 2005074602 to Bjursten et al and also in the generation of titanium peroxy compounds (Tengvall, Elwing et al. 1989; Tengvall, Lundstrom et al. 1989) with anti-inflammatory (Larsson, Persson et al. 2004) and bactericidal properties (Tengvall, Hornsten et al. 1990). The above beneficial properties of titanium seems thus to be linked to its chemical interaction with a living tissue environment.
For references of implants where titanium could be used, U.S. Pat. No. 5,015,256 (Bruce et al) discloses means and a method for fixing an elongate prosthesis, such as the stem of a femoral prosthesis, to living tissue which defines a cavity in which a length of the prosthesis is received with a gap to the boundary of the cavity. Essentially the entire gap is filled with loose, but packed grains of a biocompatible material, said grains interlocking. As an example of granular material titanium is mentioned, and the grains are stated to be irregular, essentially non-elastic and preferably porous, the latter property being said to promote growth of bone tissue which has grown from the osseous wall. The grain interlocking has been achieved by vibrating the stem into a bed of grains housed in said cavity and by a final blow on the stem.
WO00/64504 (Bruce et al) discloses a biocompatible, plastic or essentially non-elastic, porous body, such as a grain, with continuous porosity, the openings of cavities and the passages interconnecting them having a width of >about 50 μm for bone tissue. The term “continuous” is said to mean a porosity which allows bone tissue to grow through the porous body. The porous body may be of titanium.
One disadvantage with the inventions according to U.S. Pat. No. 5,015,256 and WO00/64504 is the fact that the grains according to these inventions are not optimised for anti-inflammatory and/or antibacterial effects. In fact, U.S. Pat. No. 5,015,256 and WO00/64504 do not disclose anything about any possible anti-inflammatory and/or antibacterial effects.
The present invention aims at solving this problem by providing a modified grain or granule with enhanced anti-inflammatory and/or antibacterial effect.